IMMUNOREACTIVE MACROMOLECULES OF COCCIDIOIDES CELL TYPES

描述(申请人提供)：球孢子菌病是一种真菌呼吸道疾病，是美国西南部沙漠地区的地方性疾病。最常见的临床表现是自限性肺炎，尽管这种真菌也能够在免疫能力强的个人中建立系统性感染。T细胞介导的免疫是宿主抵御球虫感染的关键。T细胞的T辅助细胞1(Th1)亚群分泌细胞因子，激活巨噬细胞，有助于保护，而Th2细胞分泌细胞因子，刺激B细胞产生抗体，似乎对真菌病几乎没有保护作用。小鼠对免疫球虫感染的抵抗力/易感性与细胞因子反应谱之间存在相关性。已有研究表明，在BALB/c小鼠腹膜腔内攻击之前或之后，给予白介素12(IL-12)可促进干扰素(干扰素-γ)的产生，并显著降低这些动物的真菌负担。也有证据表明，IL-10的表达上调抑制了免疫反应的Th1途径的刺激，可以加剧某些品系近交系小鼠对球虫感染的易感性。我们的中心假设是，免疫球虫的毒力表型是多个基因在体内表达的结果，这些基因的产物有助于宿主组织的定植，调节宿主免疫反应以利于病原体，并维持持续的炎症反应，从而导致宿主组织损伤。该项目的主要目的是从根本上了解虫体抗原对天然免疫细胞的刺激作用，以及激活Th1或Th2免疫反应的特定细胞因子和趋化因子的产生。该项目的具体目标是研究四种免疫球虫基因产物，其中三种似乎与感染的开始和转移有关，另一种似乎促进宿主对球虫感染的保护。我们已经概述了一种多方面的方法来评估这四种基因产物对疾病发展过程的影响。我们认为，这些研究的结果将极大地促进我们对寄生虫发病机制的理解。

DESCRIPTION (provided by applicant): Coccidioidomycosis is a fungal respiratory disease which is endemic to desert regions of the Southwestern U.S. The most common clinical presentation is self-limited pneumonia, although the fungus is also capable of establishing systemic infections in immunocompetent individuals. The pivotal arm of host defense against coccidioidal infection is T cell mediated immunity. The T helper 1 (Th1) subset of T cells secretes cytokines that activate macrophages which contribute to protection, while Th2 cells secrete cytokines that stimulate B cells to produce antibodies which seem to provide little protection against the mycosis. A correlation exists between resistance/susceptibility to Coccidioides immitis infection and the profile of cytokine response elicited in mice. It has been shown that administration of interleukin (IL-12) to susceptible BALB/c mice either before or after intraperitoneal challenge promoted the production of interferon (IFN-gamma) and significantly reduced the fungal burden in these animals compared to controls. Evidence has also been presented that upregulation of IL-10 expression, which inhibits stimulation of the Th1 pathway of immune response, can exacerbate susceptibility to coccidioidal infection in certain strains of inbred mice. Our central hypothesis is that the virulence phenotype of C. immitis is the result of in vivo expression of multiple genes, the products of which contribute to colonization of host tissue, modulation of host immune response to the advantage of the pathogen, and maintenance of a persistent inflammatory response which can result in host tissue damage. The major goal of the proposed project is to develop a fundamental understanding of the influence of selected antigens of C. immitis upon the stimulation of innate immune cells and production of specific cytokines and chemokines that activate either a Th1 or Th2 immune response. The specific aims of the project are focused on studies of four C. immitis gene products, three of which appear to contribute to the initiation and metastasis of the infection, and one which stimulates host protection against coccidioidal infection. We have outlined a multifaceted approach to the evaluation of the impact of these four gene products on the course of disease development. We suggest that the results of these studies will significantly advance our understanding of the pathogenesis of C. immitis.